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We report a novel technique for separating the parasitic source ( ${R} _{\text {S}}$ ) and drain ( ${R} _{\text {D}}$ ) resistances in MISFETs using the open drain and the open source configurations based on an alternating-current(AC) signal. We conducted impedance analysis for the AC signal in the open drain for ${R} _{\text {S}}$ and the open source configuration for ${R} _{\text {D}}$ . The proposed technique is independent of the I-V equation of MISFETs with various influencing parameters for separate extraction of ${R} _{\text {S}}$ and ${R} _{\text {D}}$ through the physics-based equivalent circuit of MISFETs. So the proposed technique is applicable to every single device as long as the device is an insulated gate MISFET structure, regardless of the presence or absence of the body terminal. This technique is applied to amorphous oxide semiconductor thin-film transistors with the gate length $= 10~\mu \text{m}$ without the body contact. As a result, parasitic resistances were separately extracted to be ${R} _{\text {S}} =2.1\,\,\text{k}\Omega $ , ${R} _{\text {D}} =1.7\,\,\text{k}\Omega $ for ${W} = 600~\mu \text{m}$ , ${R} _{\text {S}} = {R} _{\text {D}} =1.1\,\,\text{k}\Omega $ for ${W} = 1000~\mu \text{m}$ , and ${R} _{\text {S}} = {R} _{\text {D}} =0.6\,\,\text{k}\Omega $ for ${W} = 2000~\mu \text{m}$ independent of gate bias.

Metformin is associated with good tumor response in preoperative concurrent chemoradiotherapy (CCRT) for rectal cancer. This study aims to demonstrate that the timing of metformin is related to the tumor response on preoperative CCRT for rectal cancer. From January 2010 to December 2017, 232 patients who underwent curative resection after preoperative CCRT were reviewed. Patients were divided into groups with or without diabetes or metformin. The timing of metformin administration was divided based on before and after initiation of chemoradiotherapy. Multivariate logistic regression analysis was used to identify predictors for tumor response. Tumor downstaging (p = 0.02) and good response rates of tumor regression grade (TRG) (p = 0.008) were significantly higher in the group administered metformin before CCRT than other groups. In the multivariate analysis, metformin administration before CCRT was a significant factor in predicting tumor downstaging (odds ratio [OR] 10.31, 95% confidence interval [CI]: 1.76 - 102.08, p = 0.02) and good TRG (OR 12.55, 95% CI: 2.38 - 80.24, p = 0.004). In patients with rectal cancer who underwent preoperative CCRT, neoadjuvant therapy of metformin before CCRT was significantly associated with good tumor response and tumor downstaging.

Recent studies show that dysregulated miRNAs play an important role in breast cancer initiation and progression. Here, we identified upregulated expression of miR-1307-3p in breast cancer tissues and that increased level of miR-1307-3p was closely correlated with lower survival rate in breast cancer patients. Consistent with clinical data, our in vitro data show that expression level of miR-1307-3p was significantly increased in breast cancer cell lines compared to human mammary epithelial cell line MCF10A. Overexpression of miR-1307-3p in MCF10A stimulated cell proliferation and caused their growth in soft agar and tumor formation in nude mice. In contrast, inhibition of miR-1307-3p suppressed breast cancer cell proliferation and their growth in soft agar and inhibited tumor formation in nude mice. Further, we identified that miR-1307-3p plays its oncogenic role through targeting SET and MYND domain-containing 4 (SMYD4) expression in breast cancer. Taken together, our findings suggest that miR-1307-3p is a oncogenic miRNA that significantly contributes to breast cancer development and progression, and inhibition of miR-1307-3p may be a novel strategy for inhibits breast cancer initiation and progression.

This dissertation consists of two empirical essays that study issues related to common ownership. The first essay provides empirical evidence of return predictability across common ownership linked firms. A common ownership momentum-based long-short strategy earns a significant average monthly abnormal returns of 78 basis points from July 1982 to June 2017. This return predictability is distinct from the previously known industry, customer-supplier, standalone- conglomerate momentum, or technology lead-lag effects. A flow-based explanation can account for the observed return predictability with the common ownership-linked returns affecting capital flows to institutional portfolios and such expected flow-induced trading influencing stock returns. In addition, the return predictability is more pronounced for focal firms with less attention from investors and more limits to arbitrage. The second essay investigates the peer effect of common ownership-linked firms on corporate dividend and investment decisions. We first show that common ownership peer firms are influential in determining U.S. firms’ dividend yield and investment capital ratio. Such an effect is distinct from the previously known industry peer effects, more pronounced among more connected firms and firms facing higher uncertainty. Overall, these findings indicate that firms imitate their peers to maintain interest from institutional investors, and/or firms mimic their peers to deal with uncertainty in their decision making.

Metastasis and chemoresistance remain major challenges in the clinical treatment of breast cancer. Recent studies show that dysregulated microRNAs (miRNAs) play an important role in metastasis and chemoresistance development in breast cancer. Herein, we identified downregulated expression of miR-708-3p in breast cancers. In particular, miR-708-3p expression was significantly decreased in specimens from breast cancer patients with metastasis compared to that in specimens from patients with no metastasis. Consistent with clinical data, our in vitro data show that miR-708-3p was more significantly decreased in invasive breast cancer cell lines. In addition, our data show that inhibition of miR-708-3p significantly stimulated breast cancer cell metastasis and induced chemoresistance both in vitro and in vivo. In contrast, overexpression of miR-708-3p dramatically inhibited breast cancer cell metastasis and enhanced the sensitivity of breast cancer cells to chemotherapy both in vitro and in vivo. Furthermore, we identified that miR-708-3p inhibits breast cancer cell epithelial-to-mesenchymal transition (EMT) by directly targeting EMT activators, including ZEB1, CDH2 and vimentin. Taken together, our findings suggest that miR-708-3p acts as a cancer suppressor miRNA and carries out its anticancer function by inhibiting EMT in breast cancer. In addition, our findings suggest that restoration of miR-708-3p may be a novel strategy for inhibiting breast cancer metastasis and overcoming the chemoresistance of breast cancer cells.

Under optical illumination of metal–insulator-semiconductor field effect transistors with insulated gate structure (MISFETs including MOSFETs and TFTs), photo-generated electron-hole pairs (ehp’s) cause the photovoltaic effect (PVE) and the photoconductive effect (PCE) in the electrical characteristics of MISFETs. In the modeling and characterization of MISFETs under optical excitation for both optical sensing and/or electro-optical characterization of traps through photonic C-V and I-V responses, it is necessary to separate the PVE from the PCE in MISFETs. In this letter, we report the modeling and separate characterization of the PVE from the PCE in MISFETs applicable to MOSFETs and TFTs. We confirmed the proposed model and the technique through experimental results adopting the different substrate contact configurations and optical power of the device under characterization. As a result, the effective surface potential change for the PCE (VPCE) and the effective substrate potential change for the PVE (VPVE) could be quantitatively extracted.

In this work, a current-to-transconductance ratio technique is proposed for simultaneous extraction of the threshold voltage (VT) and parasitic source (RS) and drain (RD) resistances in short channel metal–oxide–semiconductor field-effect transistors (MOSFETs). The proposed technique allows simultaneous extraction of RS, RD, and VT in any single MOSFET with the channel length modulation (CLM) and the structural asymmetry. The proposed method is experimentally verified through Si MOSFETs with intentional asymmetry by connecting an external resistor (Rext) to the source terminal. We experimentally confirmed that extracted RS, RD, and VT are independent of the drain bias (VDS) and intentional Rext employed for the asymmetry. We also compared the results with previously reported techniques.

Cognitive impairment is prevalent in Parkinson Disease (PD) and increasing age is a PD risk factor. Age and cognition may impact patient-reported outcome measures (PROMs) level, reliability, or validity of responses. This study investigated the relative impact of cognitive function and age on PROMs in PD. Cross-sectional data (n=676) included assessments of age, cognition (Montreal Cognitive Assessment; MoCA) and PROMIS-29 Profile (physical functioning, anxiety, depression, fatigue, sleep disturbance, social functioning, pain). Analyses examined differences by age and MoCA in: 1)Level—correlations, multivariable regressions controlling for disease severity (UPDRSmotor, PD duration), comorbidity (CIRS-G), demographics; 2)Reliability--Cronbach’s alpha, and 3)Validity--correlations of PROMIS physical function with physician assessments. Sample was age M=68.0(SD=9.1); range=36-93 years, 64% male, 87% white, 37% college educated, PD duration M=8.2(SD=6.1) years, and MoCA M=24.3(SD=4.9; range 2-30). Greater cognitive impairment was consistently associated with greater physical/mental impairment (r=.14-.45; p.8) across cognitive and age groups, except for Fatigue at MoCA.36) across cognition and age groups. Cognitive impairment in PD is associated with lower physical function and mental health levels. Reliability and validity of most PROMs in PD are neither impacted by cognition nor age.

Allium hookeri is a wild herb found mainly in the Himalayas, growing at altitudes of 1400-4200 m. A. hookeri is widely consumed as a vegetable and herbal medicine in Asia, but its effects on bone health have not been reported previously. This study investigated the effects of a hot-water extract of A. hookeri roots on bone formation. The hot-water extract significantly increased the proliferation of in vitro human osteoblast-like MG-63 cells and the stimulatory effects on osteoblast differentiation were noticeably greater for the hot-water extract than for daidzein (a positive control), as reflected by alkaline phosphatase activity, collagen content, and mineral deposition. Expression of the bone-remodeling marker osteocalcin production and bone microstructural parameters were significantly improved in Sprague-Dawley rats in vivo after oral treatment with the hot-water extract compared with their control (saline-administered) counterparts. The chemical compounds of the hot-water extract were characterized by liquid chromatography-mass spectrometry, and alliin, sinapic acid, and ferulic acid, which exert beneficial effects on bone health, were identified. These findings indicate that A. hookeri can be used as a natural resource for increasing bone formation. This is the first report of the anabolic effects of A. hookeri extracts on bone formation in vitro and in vivo.

It is important to characterize the distribution of spatial traps in the MOS structure for separating the interface states from the subgap density-of-states. In this study, we report a characterization technique for the spatial distribution of traps using the C-V characteristics under deep-depletion bias. Depletion capacitance is determined by the depletion depth (Xd) and the dielectric constant with the MOS structure. Thus, the distribution of spatial depletion charges can be identified if only the depletion capacitance can be separated from the measured gate capacitance. In the case of MOS structure with spatial traps in the element, it will show a deviated characteristic from the ideal depletion capacitance. Therefore, this allows us to characterize the spatial distribution of traps in MOS structures. The spatial distribution of traps from a single crystal silicon MOS capacitor was extracted Ntrap,max = 3.45 × 1018 cm−3 ass the maximum value in the interface, indicating that the concentration tends to decrease more in the substrate direction.

Turnip (Brassica rapa L.) root ethanol extract (TRE) was prepared, and its chemical constituents were characterized by ultra-performance liquid chromatography and mass spectrometry. Thirteen glucosinolates (GSLs) were identified, comprising eight aliphatic, four indolic, and one aromatic compounds. The effects of these GSLs on bone formation were investigated in vitro by incubating human osteoblast-like MG-63 cells with TRE and then analyzing their viability, alkaline phosphatase (ALP) activity, collagen content, and mineralization and in vivo by administering TRE orally to normal young rats (500 mg/kg/day) and assessing subsequent changes in serum osteocalcin and bone microstructure in these animals. No TRE-related toxicity was found, and the levels of cell viability, ALP activity, collagen synthesis, and mineralization were significantly increased relative to the negative control. In particular, stimulatory effects on the differentiation of MG-63 cells were strongly enhanced as compared with a positive control (daidzein). Serum osteocalcin was also significantly increased, and some important bone microstructural parameters were improved in TRE-administered rats compared with their saline-administered counterparts. GSLs therefore appear to have a stimulatory effect on bone formation in both MG-63 cells and normal young rats. This is the first report on the usefulness of turnip root and its GSL compounds for bone formation. Copyright © 2015 John Wiley & Sons, Ltd.

Recently, as the interest of location based services has increased, research on indoor positioning technology has been actively conducted. In particular, methods on fingerprinting that is less affected by obstacles has become a promising approach. In this paper, we propose a method to reduce positioning errors in the important access point selection method for fingerprint localization by spatial partitioning.

Chemotherapy-induced cognitive impairment (CICI) is increasingly recognized as a major unwanted side effect of an otherwise highly valuable life-saving technology. In part, this awareness is a result of increased cancer survival rates following chemotherapy. Altered hippocampal neurogenesis may play a role in mediating CICI. In particular, zinc could act as a key regulator of this process. To test this hypothesis, we administered paclitaxel (Px) to male C57BL/6 mice for set time periods and then evaluated the effects of Px treatment on hippocampal neurogenesis and vesicular zinc. We found that vesicular zinc levels and expression of zinc transporter 3 (ZnT3) were reduced in Px-treated mice, compared to vehicle-treated mice. Moreover, Px-treated mice demonstrated a significant decrease in the number of neuroblasts present. However, no difference in the number of progenitor cells were observed. In addition, zinc supplementation by treatment with ZnCl2 ameliorated the Px-induced decrease in hippocampal neurogenesis and cognitive impairment. These results suggest that via disruption of vesicular zinc stores in hippocampal mossy fiber terminals, chemotherapy may impinge upon one or more of the sequential stages involved in the maturation of new neurons derived via adult neurogenesis and thereby leads to the progressive cognitive decline associated with CICI.

Most known osteoporosis medicines are effective for bone resorption, and so there is an increasing demand for medicines that stimulate bone formation. Watercress (N. officinale R. Br.) is widely used as a salad green and herbal remedy. This study analyzed a watercress extract using ultra-performance liquid chromatography/mass spectrometry, and identified a rutin as one of its major constituents. Osteogenic-related assays were used to compare the effects of watercress containing rutin (WCR) and rutin alone on the proliferation and differentiation of human osteoblast-like MG-63 cells. The reported data are expressed as percentages relative to the control value (medium alone; assigned as 100%). WCR increased cell proliferation to 125.0±4.0% (mean±SD), as assessed using a cell viability assay, and increased the activity of alkaline phosphatase, an early differentiation marker, to 222.3±33.8%. In addition, WCR increased the expression of collagen type I, another early differentiation marker, to 149.2±2.8%, and increased the degree of mineralization, a marker of the late process of differentiation, to 122.9±3.9%. Rutin alone also increased the activity of ALP (to 154.4±12.2%), the expression of collagen type I (to 126.6±6.2%), and the degree of mineralization (to 112.3±5.0%). Daidzein, which is reported to stimulate bone formation, was used as a positive control; the effects of WCR on proliferation and differentiation were significantly greater than those of daidzein. These results indicate that WCR and rutin can both induce bone formation via the differentiation of MG-63 cells. This is the first study demonstrating the effectiveness of either WCR or rutin as an osteoblast stimulant.

Background: Both cosmetic and oncologic outcomes are becoming more important for breast cancer patients. Breast-conserving surgery (BCS) has an acceptable cosmetic result compared with mastectomy, but BCS is also associated with cosmetic failure. In this study, we evaluated the cosmetic outcome of reconstructive surgery with the absorbable implant vicryl mesh after BCS compared with the outcome of BCS alone. Methods: From May 2007 to December 2009, 101 patients were involved in this study at Hallym University Sacred Heart Hospital. We used absorbable implants made of folding vicryl mesh and wrapped them with Interceed. In 79 cases, BCS with vicryl mesh implantation was performed; in the other 56 cases, only BCS was performed. Patient satisfaction with cosmetic outcomes was evaluated. We also analyzed other factors that affected cosmetic outcomes, including patient ages, body mass indices, tumor locations, and removed breast tissue. Results: In the vicryl mesh implantation group, 65 of 79 patients (82.3%) were satisfied; in the BCS-only group, 24 of 56 patients (43%) were satisfied (P < 0.05). In the vicryl mesh implantation group, patient ages, body mass indices, and removed breast tissue did not affect cosmetic outcomes. When the tumor was located in the upper outer quadrant, the patients were more satisfied (P < 0.05). Conclusions: Reconstructive procedures with vicryl mesh are simple, safe, and less expensive than other plastic reconstruction techniques. This study suggests that the procedure was superior to BCS alone in cosmetic outcomes. We believe that the procedure could become a favorable technique in oncoplastic surgery. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-15-11.

Turnip (Brassica rapa L.) root ethanol extract (TRE) was prepared, and its chemical constituents were characterized by ultra-performance liquid chromatography and mass spectrometry. Thirteen glucosinolates (GSLs) were identified, comprising eight aliphatic, four indolic, and one aromatic compounds. The effects of these GSLs on bone formation were investigated in vitro by incubating human osteoblast-like MG-63 cells with TRE and then analyzing their viability, alkaline phosphatase (ALP) activity, collagen content, and mineralization and in vivo by administering TRE orally to normal young rats (500 mg/kg/day) and assessing subsequent changes in serum osteocalcin and bone microstructure in these animals. No TRE-related toxicity was found, and the levels of cell viability, ALP activity, collagen synthesis, and mineralization were significantly increased relative to the negative control. In particular, stimulatory effects on the differentiation of MG-63 cells were strongly enhanced as compared with a positive control (daidzein). Serum osteocalcin was also significantly increased, and some important bone microstructural parameters were improved in TRE-administered rats compared with their saline-administered counterparts. GSLs therefore appear to have a stimulatory effect on bone formation in both MG-63 cells and normal young rats. This is the first report on the usefulness of turnip root and its GSL compounds for bone formation.

To overcome the therapeutic restrictions offered by hydrophobic quercetin (Qu), this study aims to synthesize MPEG-PLA encapsulated Qu nanoparticle and to evaluate their anticancer efficacy. In vitro anticancer potential and apoptotic studies were done by cell cytotoxicity assay and flow cytometry, respectively. MPEG-PLA-Qu nanoparticles were evaluated for anticancer efficacy in vivo using xenograft mice model. TUNEL assay was performed to observe the frequency of apoptotic cells in vivo. The hydrodynamic particle size, polydispersity index, zeta potential and drug loading % of MPEG-PLA-Qu nanoparticle was 155.3 ± 3.2 nm, 0.2 ± 0.05, −3.14 mV and 5.3 ± 1.1%, respectively. Also, MPEG-PLA-Qu showed sustained drug release for 10 days. In vitro results showed that MPEG-PLA-Qu could efficiently induce apoptosis in triple negative breast cancer cell line (MDA-MB-231) with higher amount of quercetin in cell lysate treated with MPEG-PLA-Qu in comparison to free quercetin. In xenograft model for breast cancer, peritumorally injected MPEG-PLA-Qu significantly inhibited the tumor growth. Moreover, TUNEL assay showed more occurrence of apoptotic cells in MPEG-PLA-Qu treated tumors compared to free quercetin at similar dose. Our data suggest that MPEG-PLA-Qu nanoparticle can have a promising clinical potential for the treatment of breast cancer.

Quercetin is a promising chemopreventive agent against cancer that inhibits tumor progression by inducing cell cycle arrest and promoting apoptotic cell death. Recently, the Wnt/β-catenin signaling pathway has been implicated in mammary tumorigenesis, where its abnormal activation is associated with the development of breast cancer. Thus, the objective of this study was to examine the biological activities of quercetin against mammary cancer cells, and to determine whether quercetin could regulate the Wnt/β-catenin signaling pathway. Quercetin showed dose-dependent inhibition of cell growth and induced apoptosis in 4T1 cells. Treatment of 20 µM quercetin suppressed ~50% of basal TopFlash luciferase activity. Moreover, the inhibitory effect of quercetin on the Wnt/β-catenin signaling pathway was confirmed by the reduced stabilization of the β-catenin protein. Among various antagonists screened for the Wnt/β-catenin signaling pathway, the expression of DKK1, 2 and 3 was induced after treatment with 20 µM of quercetin. Stimulation with recombinant DKK1 protein, showed suppressive cell growth of mammary cancer cells instead of quercetin. When 4T1 cells were treated with recombinant Wnt3a or LiCl along with quercetin, both stimulators for the Wnt/β-catenin signaling pathway were able to restore the suppressed cell viability by quercetin. Thus, our data suggest that quercetin exerts its anticancer activity through the downregulation of Wnt/β-catenin signaling activity. These results indicate for the first time that quercetin decreases cell viability and induces apoptosis in murine mammary cancer cells, which is possibly mediated by DKK-dependent inhibition of the Wnt/β-catenin signaling pathway. In conclusion, our findings suggest that quercetin has great potential value as chemotherapeutic agent for cancer treatment, especially in breast cancer controlled by Wnt/β-catenin signaling activity.

Solidago virga-aurea (European goldenrod or woundwort) is an herbaceous perennial plant of the family Asteraceae. It is used for medical system with astringent, diuretic, antiseptic and homeopathic properties. And the studies about Solidago virga-aurea are in progress for the other functions. Recently, we found that Solidago virga-aurea extract induces apoptosis of breast cancer cells. MTT assay showed that cellular viability was decreased in Solidago virga-aurea extract treated MDA-MB-231 and MCF-7 breast cancer cell lines by dose and time dependent manner. And apoptotic protein, especially bim, was increased in Solidago virga-aurea extract treated MCF-7 cell line. However, anti-apoptotic protein, Bcl-xL, does not changed by Solidago virga-aurea extract. In order to find out positive regulator of bim expression, we tested whether FOXO (forkhead-box transcription factor, group O) 3a and AMPK (5’ AMP-activated protein kinase) protein expression. In immunoblot analysis showed that FOXO3a expression level was dramatically increased in Solidago virga-aurea treated MCF-7 cells without changes of AMPK expression. Moreover, immunostaining showed that Solidago virga-aurea induces co-localization of FOXO3a and bim proteins in MCF-7 and MB-231 cells. Taken together, Solidago virga-aurea induces apoptosis by FOXO3a mediated up-regulation of bim protein. The mechanisms of Solidago virga-aurea mediated FOXO3a regulation is not fully elucidated yet, but further studies about this molecular mechanism between two proteins will give some ideas for cancer therapies for certain breast cancer patients. Citation Format: Haesung Kim, Chea Ha Kim, Jeong-Hyeon Kim, Jeong-Min Lee, Jeong-Ho Jeon, Jae-Yong Lee. Solidago virga-aurea extract induced apoptosis of breast cancer cells through FOXO3 mediated bim expression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3520.

Past studies using artificial language speech streams showed that adults use statistics to correctly segment words. However, these studies mostly used only a single stream input and monolingual populations. Given the number of bilinguals and the prevalence of exposures to multiple languages, how do monolinguals and bilinguals compare in speech segmentation task given multiple inputs? Speech segmentation becomes challenging with multiple inputs when learners combine input across languages. The statistics of particular units that overlap different languages may change and hinder correct segmentation. Current study addresses this question by using two interleaved artificial language streams and an indexical accent cue. In the study, participants were asked to segment two artificial language streams with or without an accent cue. Our results indicated that in the absent of the accent cue, bilinguals and monolinguals performed similar, while monolinguals’ performance was weakened compared to those of bilinguals in the presence of the accent cue. Weakened performance can be due to two accounts: switching of accents and difficulty of languages. This study, expanding Weiss et al. (2009) and bilingualism research, informs us that the level of difficulty of languages and cues can play a role in segmenting multiple language streams.

This study examined the roles played by parental alcohol abuse and social support, peer substance abuse risk and social support, and substance abuse risk among adolescents in South Korea. Participants were adolescents between the ages of 15 and 22 years (mean, 18), residing in Seoul city and in surrounding Kyung-gi Province. Of 259 participants, 41.3% scored 2 or more on the POSIT scale, which suggested they met the problematic criteria for substance abuse risk. Logistic regression results suggested that the influence of social support on substance abuse risk among adolescents depended on the source of support--parents or peers. These findings need to be considered in the development of intervention programs for adolescents at risk for substance abuse.

Breast cancer is the most common cancer in the women. Recent study revealed that nucleotide excision repair (NER) deficiency might play an important role in the cause of sporadic breast cancer, showing significant reduction of five NER gene products including xeroderma pigmentosum group C (XPC) in human breast cancer tissue. Thus, XPC inactivation might be related to occurrence and progression of breast cancer. FoxP1 is a member of the forkhead O family of transcription factors which have a broad range of functions. FoxP1 is considered as a putative tumor suppressor in breast cancer because of its ability to cause apoptosis. The relationship between FoxP1 and XPC has been yet to be known in breast cancer. In our data, Western blot analysis of 8 human primary tumors showed that the high expression of FoxP1 was correlated with the high level of XPC. In three established mammary epithelial cell lines (MCF-7, MDA-MB-231, 4T1), FoxP1 expression in MCF-7 was higher than in MDA-MB-231 and 4T1. Similar to the result of primary tumors, the expression of XPC was also high in MCF-7 and low in MDA-MB-231 and 4T1. Next, we found that the level of XPC decreased with the knockdown of FoxP1 compared to control in MCF-7. On the other hand, the ectopic expression of FoxP1 in MDA-MB-231 and 4T1 elevated XPC expression for protein level. In real time RT-PCR, the level of XPC mRNA was the same as in Western blot analysis. We tested whether NER activity is dependent on FoxP1. In vitro NER activity increased by overexpression of FoxP1 in MB-231. Sh-FoxP1 transfected MCF-7 cell shows reduced in vitro NER activity. In addition, immunostaining assay showed that XPC expression was much accumulated in the nucleus of MDA-MB-231 with overexpression of FoxP1 than in control.Taken together, these data suggested FoxP1 could up-regulate NER activity by activating XPC in breast cancer. However, the way how FoxP1 can regulate XPC remained to be cleared. To clarify the mechanism, we are performing biological interaction between FoxP1 and XPC in both breast cancer cell lines and human primary breast tumors. Citation Format: Haesung Kim, Lee-Su Kim, Jae-yong Lee, Jeong-Hyeon Kim, Jeong-Min Lee, Chea-Ha Kim. FoxP1 increases nucleotide excision repair capacity through activating xeroderma pigmentosum group C in human breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3021. doi:10.1158/1538-7445.AM2015-3021

Transforming growth factor beta (TGF-beta) type-II receptor mutations have been reported in several epithelial-type human malignancies. To elucidate the role of TGF-beta RII in lung cancer progression, we prepared gene-modified clones of the human lung cancer cell line NCI-H23. NCI-H23, a human non-small-cell lung adenocarcinoma cell line which has a frameshift mutation in, and reduced expression of, the TGF-beta type-II receptor (TGF-beta RII), exhibits resistance to growth inhibition by TGF-beta(1) in vitro. Transfection of NCI-H23 with a retroviral vector expressing wild-type TGF-beta RII restored the responsiveness of cells to exogenous TGF-beta(1) with reduced cell proliferation. Immunocytochemical analysis demonstrated nuclear translocation of Smad3 after TGF-beta(1) treatment in RII-restored NCI-H23 cells. Underphosphorylation of the retinoblastoma protein accompanying p21 up-regulation was observed after TGF-beta(1) treatment of NCI-H23-RII cells. Receptor restoration also changed the levels of VEGF mRNA induced by TGF-beta(1). However, impairment of TGF-beta signalling did not alter microvessel formation in vivo in transplanted tumours. Instead, in vivo tumorigenesis experiments revealed a remarkable difference in the number and sizes of the tumours derived from NCI-H23-RII cells and dominant negative NCI-H23-dnRII cells (P < 0.01). Collectively, these observations suggest that impairment of TGF-beta signal transduction contributes significantly to tumour progression, mainly by cell proliferation rather than by modulation of angiogenesis in human NCI-H23 lung carcinoma cells.

Forkhead box O (FoxO) transcription factors play an important role in multiple signaling pathways and physiological and pathological processes including apoptosis, proliferation metabolism, immunity, and tumorigenesis. Activation of the FoxO subfamily in cells can upregulate cell-cycle inhibitors p21Cip1 and p27Kip1 and downregulate the cell-cycle regulator cyclin D1/2, consequently leading to G1/S arrest of cells. Recently, quercetin has attracted much attention in relation to its anticancer activities in many cancer models, however, molecular mechanisms underlying quercetin-mediated cellular responses remain poorly defined. We have previously observed that apoptosis of breast cancer cells in response to quercetin was mediated by transcriptional activation of Foxo3a. In addition, C-Jun N-treminal kinase (JNK) regulated the activation of FoxO3a, leading to apoptosis. However, early apoptotic cells stained with Annexin V were not enough to illustrate the whole amount of decreased cell viability as detected by MTT assay. To clarify this point, we analyzed changes of their cell cycle after stimulation of 20μM quercetin and detected obvious cell cycle arrest at S and G2/M phases leading to delay in their progression. Treatment of quercetin resulted in 3 fold induced population of S phase and 2 fold induced population of G2/M phase, along with 35 % reduced population of G1 phase. Using luciferase reporter assay, MDA-MB231 cells treated with quercetin represented highly increased level of p53, p21 and GADD45 signaling activity, which control cell cycle of breast cancer cells. Moreover, reporter activities of p53, p21 and GADD45 were not stimulated when the expression of Foxo3a was abolished using transfection of Foxo3a shRNA. Since the activation of Foxo3a coincided with increased phosphorylation of JNK after treatment of quercetin, signaling pathways for cell cycle were analyzed in the presence of inhibitor for JNK (SP600125). SP600125 reversed the activation of p53, p21 and GADD45 signaling as well as the activation of Foxo3a. Flow cytometry revealed that quercetin-induced cell cycle arrest of MDA-MB231 cells was partially abrogated when cells were treated with SP600125.Taken together, our data show that cell cycle arrest of breast cancer cells in response to quercetin is dependent upon Foxo3a activation regulated by JNK, resulting in the activation of p53, p21 and GADD45 signaling pathways. These results suggest that an understanding of precise molecular mechanisms for anti-cancer property of quercetin . Citation Format: Hae-Sung Kim, Ju-Suk Nam, Sang Su Lee, Lee-Su Kim, Byung-Yoon Ryu, Hee-Joon Kang, Byung-Su Choi, Bilguun Ganbold, Yun-Cheol Ko. Foxo3a regulates cell cycle arrest through the regulation of p53, p21 and GADD45 signaling activity in Quercetin-treated MDA-MB-231 breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 564. doi:10.1158/1538-7445.AM2013-564